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Kenton M. Sanders, Ph. D.Professor and Chairman
I have been interested in smooth muscle physiology and pharmacology for most of my career. As a student, I became interested in electrical rhythmicity in smooth muscles, and I have devoted most of my efforts to trying to understand the mechanisms responsible for this activity. Like the heart, many smooth muscles have spontaneous rhythmicity. We now think that a special class of pacemaker cells, interstitial cells of Cajal (ICC), drives this activity in gastrointestinal smooth muscles and oviduct. I have collaborated with Drs. Sean Ward and Sang Don Koh for several years on the study of ICC. We have used electrophysiology, optical imaging techniques, molecular biology, confocal and electron microscopy, and several other techniques to study the structure and function of ICC. These cells are present in pacemaker areas of the GI tract and oviduct. ICC are excitable cells that are spontaneously active after they have been dispersed from intact muscles. We have made a transgenic mouse in which ICC are are labeled with a fluorescent protein (copGFP). The rhythmicity of GI and oviduct muscles stops when ICC are damaged or lost. We are also studying the development of ICC and trying to understand what happens to these cells in certain types of GI motility disorders, such as the defects in motility that occurs in diabetes. Look at our reviews in Gastroenterology (111:492-515, 1996) or Neurogastroenterology and Motility (11:311-38, 1999, and Ann Rev Physiology (68:307-43, 2006). if you want to learn more about ICC and the progress that has been made on these cells. I've also been interested in neural control of smooth muscles. In the case of GI muscles important behaviors of intact organs and tissues are controlled by excitatory and inhibitory motor neurons. We have spent considerable effort trying to understand how the transmitter substances released by neurons affects electrical rhythmicity, intracellular calcium transients, and contractions. We have studied the effects of nitric oxide (NO) broadly and characterized post-junctional responses and molecular regulation of ion channels in response to NO released from neurons. Recently we have also been working on the other major inhibitory neurotransmitter, a purine, which for many years has been thought to be ATP. We have recently reported that B-NAD is actually a better candidate for this transmitter as the effects of exogenous ATP do not mimic the effects of the substance released from neurons. We also now recognize that ICC are innervated and participate in neurotransmission in GI muscles. Thus, loss of these cells may reduce regulation of GI motility by excitatory and inhibitory nerves. Much of our work on the role of neurotransmitters has focused on how these substances affect the ionic conductances in smooth muscle cells or ICC that are responsible for electrical responses. We have used the patch clamp technique extensively for these studies and molecular techniques to attempt to understand the targets of neurotransmitter actions. Search For Dr. Sanders' Publications In PubMed Selected Publications -- Langton, P.D., S. Ward, M. Norell and K.M. Sanders. (1989) Spontaneous electrical activity from interstitial cells of Cajal isolated from canine proximal colon. Proc. Nat. Acad. Sci. 86:7280-7284. -- Thornbury, K.D., S.M. Ward, H.H. Dalziel, A. Carl, D.P. Westfall and K.M. Sanders. (1991) Nitric oxide and nitrosocysteine mimic non-adrenergic, non-cholinergic hyperpolarization in gastrointestinal muscles. Am. J. Physiol. 261:G553-G557. -- Lee, H.K. and K.M. Sanders. (1993) Comparison of ionic currents from interstitial cells and smooth muscle cells of canine colon. Journal of Physiology 460:135-152. -- Publicover, N.G., E.M. Hammond and K.M. Sanders. (1993) Amplification of nitric oxide signalling by interstitial cells. Proc. Nat. Acad. Sci. 90:2087-2091. -- Ward, S.M., A.J. Burns, S. Torihashi and K.M. Sanders. (1994) Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in the murine intestine. J. Physiology (Rapid Communication). 480:91-97. -- Burns, A.J., A.E.J. Lomax, S. Torihashi, K.M. Sanders and S.M. Ward. (1996) Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc. Nat. Acad. Sci. (USA) 93:12008-12013. -- Torihashi S., K. Nishi, Y. Tokutomi, T. Nishi, S.M. Ward and K.M. Sanders (1999) Blockade of Kit signaling induces transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotype. Gastroenterology. 117: 140-148. -- Ördög, T., I. Takayama, W.K.T. Cheung, S.M. Ward and K.M. Sanders. (2000) Remodeling of networks of interstitial cells of Cajal in diabetic gastroparesis. Diabetes. 49: 1731-1739. -- Ward, S.M., E.A.H. Beckett, X-Y. Wang, F. Baker, M. Khoyi and K.M. Sanders. (2000) Interstitial cells of Cajal mediate enteric excitatory neurotransmission in the murine fundus. Journal of Neuroscience 20:1393-1403. -- Ward, S.M., T. Ördög, S.D. Koh, S. Abu Baker, J.Y. Jun, G. Amberg, K. Monaghan and K.M. Sanders. (2000) Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. Journal of Physiology (Rapid Report) 525: 355-361. -- Bayguinov, O, B. Hagen, A.D. Bonev, M.T. Nelson and K.M. Sanders. (2000) Intracellular calcium events activated by ATP in murine colonic myocytes. American Journal of Physiology - Cell 279: C126-135. -- Bayguinov, O, B. Hagen, J.L. Kenyon and K.M. Sanders. (2001) Coupling strength between localized Ca2+ transients and K+ channels is regulated by protein kinase C. American Journal of Physiology: Cell Physiology. 281: C1512-1523. -- Koh, S.D. and K.M. Sanders (2001) Stretch-dependent potassium channels in murine and canine colonic smooth muscle cells. Journal of Physiology 533: 155-163. -- Dick, G.M. and K.M. Sanders. (2001) [Xeno]estrogen-sensitivity of smooth muscle BK channels conferred by the regulatory ß1 subunit: A study of ß1 knockout mice. J Biological Chemistry 276: 44835-44840. -- Kim, Y.C., S.D. Koh and K.M. Sanders. (2002) Voltage-dependent inward currents of interstitial cells of Cajal from murine colon and small intestine. Journal of Physiology 541: 797-810. -- Koh, S.D., J.Y. Jun, T.W. Kim and K.M. Sanders. (2002) A Ca2+-inhibited non-selective cation conductance contributes to pacemaker currents in cultured interstitial cells of Cajal. Journal of Physiology 540: 803-814. -- Ördög, T., M. Baldo, R. Danko and K.M. Sanders. (2002) Plasticity of electrical pacemaking by interstitial cells of Cajal underlies gastric dysrhythmia in W/WV mutant mice. Gastroenterology 123: 2028-2040. -- Kim, T.W., S.D. Koh, T. Ördög and K.M. Sanders (2003) Muscarinic regulation of pacemaker frequency in gastric interstitial cells of Cajal. Journal of Physiology 546: 415-425. -- Ward, S.M., S.A. Baker, A. de Faoite and K.M. Sanders. (2003) Propagation of slow waves requires regeneration via IP3 receptors and mitochondrial Ca2+ uptake mechanism in canine colonic muscles. Journal of Physiology 549: 207-218. -- Hagen, B, O. Bayguinov and K.M. Sanders. (2003) ß1 subunits are required for regulation of coupling between Ca2+ transients and Ca2+ activated K+ (BK) channels by protein kinase C. American Journal of Physiology - Cell Physiology 285: C1270-C1280. -- Amberg, G.C., S.D. Koh, Y. Imaizumi, S. Ohya, and K.M. Sanders. (2003) A-type potassium currents in smooth muscles. American Journal of Physiology – Cell Physiology. Invited Review. 284: C583-C595. -- Ördög, T., Redelman, D., Miller, L.J., Horváth, V.J., Zhong, Q., Graça Almeida-Porada, G., Zanjani, E.D., Horowitz, B. and Sanders, K.M. (2004) Purification of interstitial cells of Cajal by fluorescence-activated cell sorting. American Journal of Physiology: Cell Physiology 286: C448-456. -- Won K-J, Sanders KM, Ward SM. (2005) Interstitial cells of Cajal mediate mechano-sensitive responses in the stomach. Proceedings of the National Academy of Science (USA) 102: 14913-14918. -- Cho SY, Beckett EA, Baker SA, Han I, Park KJ, Monaghan K, Ward SM, Sanders KM, Koh SD. (2005) A pH-sensitive potassium conductance (TASK) and its function in the murine gastrointestinal tract. Journal of Physiology 565: 243-259. -- Kito Y, Ward SM, Sanders KM. (2005) Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine. American Journal of Physiology: Cell Physiology 288: C710-720. -- Sanders KM, Koh SD, Ward SM. (2006) Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annual Review of Physiology 68:307-343. -- Sanders KM (2006) Interstitial cells of Cajal at the clinical and scientific interface. Journal of Physiology 576:683-687. -- Park KJ, Hennig GW, Lee H-T, Spencer NJ, Ward SM, Smith TK, Sanders KM (2006) Spatial and temporal mapping of pacemaker activity in interstitial cells of Cajal in mouse ileum in situ. American Journal of Physiology: Cell Physiology 290:C1411-C1427. -- Ward SM, Sanders KM (2006) Involvement of intramuscular interstitial cells of Cajal in neuroeffector transmission in the gastrointestinal tract. Journal of Physiology 576:675-682. -- Chen H, Redelman D, Ro S, Ward SM, Ordog T, Sanders KM (2007) Selective labeling and isolation of functional classes of interstitial cells of Cajal of human and murine small intestine. Am J Physiol Cell Physiol. 292:C497-507.
-- Sanders KM, Ward SM (2007) Kit mutants and
gastrointestinal physiology. Journal of Physiology
578:33-42.
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